Ovarian carcinoma remains the most lethal gynecologic malignancy. It has been reported to be the fifth most common cancer and the fourth leading cause of cancer mortality among women in the United States(Maller, B. A., et al., SEER Cancer Statistics Review: 1973-1990, Bethesda, Md., National Cancer Institute(1993)).
Due to the lack of powerful diagnostic tests and also to the absence of any overt symptoms, early detection of ovarian cancer is difficult. In approximately two-thirds of patients, the disease is at an advanced stage(III or IV) at the time of diagnosis(Boring, C. C., et al., "Cancer Statistics", Ca. Cancer J. Clin., 44, 7-26(1994); Coppleson, M., et al., Gynecologic Oncology: Fundamental Principles and Clinical Practice, 2nd ed, London, Churchill Livingstone Press(1992); and Hung, Y. C., et al., "The Female Reproductive System: Cell Lines from Tumor of the Human Ovary and Uterus", in Hay, R. J., et al., Atlas of Human Tumor Cell Lines, Academic Press, San Diego, pp 359-386(1994)). Currently, no effective treatment strategies exist, and the long-term prognosis for patients with advanced disease has not improved significantly over the last ten years.
All of these clinical problems are due primarily to a poor understanding of the biological behavior of this tumor. The development of new strategies for diagnosis and treatment must be based on a sound scientific foundation, and in this line, it is very important to have clinically relevant in vitro models to help us study the biology of this malignant disease. The establishment of permanent human ovarian carcinoma cell lines is essential for a multitude of in vitro investigations, while such cultured cancer cell lines can also be used for the production of tumor-associated monoclonal antibodies which can be used for detecting and monitoring the disease(Kabawat, S. E., et al., "Immunopathologic Common Surface Antigens of Human Ovarian Tumors of Serous Endometrioid and Clear Cell Types", Am. J. Clin. Pathol., 79, 98-104(1983)).
Numerous studies on ovarian carcinomas have reported genetic alterations in oncogenes and tumor suppressor genes(Piver, M. S., et al., "Epidemiology and Etiology of Ovarian Cancer, Semin. Oncol., 18, 177-185(1991)). Specifically, amplification or activation of the oncogenes HER-2/neu, K-ras and c-myc, as well as inactivation of the tumor suppressor genes p53, BRCA1 and the human mismatch repair genes hMLH1, hMSH2, hPMS1 and hPMS2, have been detected in ovarian cancers.
Mutation of the p53 gene, often accompanied by overexpression of mutant p53 protein, is the most frequent molecular genetic event described to date in human cancers(Greenblatt, M. S., et al., "Mutations in the p53 Tumor Suppressor Gene: Clues to Cancer Etiology and Molecular Pathogenesis", Cancer Res., 54, 4855-4878(1994)). It has been reported that mutation of the p53 gene occurs in about 30-50% of ovarian cancers(Berchuck, A., et al., "The p53 Tumor Suppressor Gene Frequently Altered in Gynecologic Cancers, Am. J. Obstet. Gynecol., 170, 246-252(1994)).
Well-established and characterized permanent human ovarian carcinoma cell lines can therefore provide useful tools for in vitro studies related to human ovarian carcinomas, but no cell line containing inactivated tumor suppressor gene BRCA1 has been successfully established heretofore.
Accordingly, there exists a need to develop a novel permanent human ovarian carcinoma cell line.